Ascorbic acid as a pharmacologic agent in disease treatment

抗坏血酸作为疾病治疗中的药物

• 批准号: 8553521
• 负责人: MARK A LEVINE
• 金额: $ 46.32万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553521
• 关键词: Acids; Advanced Malignant Neoplasm; Animal Model; Animals; Ascorbic Acid; Biological Availability; Blood; Bypass; Case Series; Cell Death; Cessation of life; Clinic; Clinical; Clinical Trials; Consumption; Coupled; DNA Damage; Data; Disease; Dose; Evaluation; Excretory function; Extramural Activities; Generations; Glutathione; Homeostasis; Human; Hydrogen Peroxide; Image; In Vitro; Intravenous; Investigation; Kidney; Laboratories; Light; Malignant Neoplasms; Mediating; Membrane; Metals; Mitochondria; Molecular Mechanisms of Action; Normal Cell; Oral; Outcome; Pathologic; Patients; Pattern; Peroxidases; Phase I Clinical Trials; Phase II Clinical Trials; Physicians; Physiological; Placebo Control; Plasma; Play; Poly(ADP-ribose) Polymerases; Prodrugs; Proteins; Publishing; Reactive Oxygen Species; Recommended Dietary Allowance; Research Personnel; Role; Safety; Therapeutic; Time; Tissues; Toxic effect; absorption; animal data; ascorbate; base; cancer cell; cancer therapy; chemical synthesis; design; double-blind placebo controlled trial; extracellular; in vivo; intravenous administration; killings; novel; oxidation; pharmacokinetic model; prevent; repaired; research study; tumor growth

Explanation When ingested orally, ascorbic acid is tightly controlled by three physiologic mechanisms: absorption, tissue transport, and renal reabsorption/excretion. Intravenous administration of ascorbic acid bypasses tight control until the kidney restores homeostasis, as determined from bioavailability experiments conducted by this laboratory. These data have surprising and novel implications for cancer treatment. More than 30 years ago, Ewan Cameron proposed that ascorbic acid might have a beneficial effect in treating patients with cancer. Joined by the two-time Nobel Laureate Linus Pauling, they published two case series indicating potential benefit of a large daily dose of ascorbic acid, 10 grams, in some patients with terminal cancer. Note for comparison purposes that the recommended dietary allowance for ascorbic acid at that time was 60 mg daily, or 0.6% of the treating dose. The Cameron-Pauling data were criticized because they were retrospective, without placebo control, in part subjective, and lacked independent pathologic confirmation. Investigators at the Mayo Clinic conducted two double blind, placebo controlled trials using 10 grams ascorbate daily to treat patients with advanced cancer, and found no effect. Based on these data, physicians were strongly advised to not use ascorbic acid in cancer treatment. In light of our extensive bioavailability data, we reviewed the experiments of Cameron and colleagues, and the Mayo Clinic investigators. We were astonished to recognize that the Cameron-associated patients received IV and oral ascorbic acid, but the Mayo Clinic-associated patients received only oral ascorbic acid. Thus, comparisons between the treatment groups were invalid, and the issue of ascorbic acid in cancer treatment needed re-evaluation. Based on our bioavailability data and pharmacokinetics modeling, intravenous ascorbic acid dosing can produce plasma concentrations as much as 70 fold higher than maximally tolerated oral doses. In vitro, pharmacologic ascorbic acid concentrations that are easily achieved in humans kill cancer but normal cells. Killing is mediated by extracellular ascorbic acid, its oxidation to ascorbate radical, and protein-dependent formation of hydrogen peroxide. To detect hydrogen peroxide without ascorbate interference, experiments required specialized chemical synthesis of peroxyxanthones, not commercially available. Based on the obtained data, we proposed and validated in vivo the hypothesis that pharmacologic ascorbic acid is a pro-drug for preferential formation of ascorbate radical in the extravascular space, but not blood. Again, in vivo experiments were dependent on synthesis of peroxyxanthones. Concurrently, we developed a global hypothesis explaining why cancer but not normal cells are sensitive to ascorbate mediated death via hydrogen peroxide formation. Hydrogen peroxide in the presence of ascorbate and catalytic metals leads to formation of multiple reactive oxygen species (ROS). Reactive oxygen species thus formed may selectively kill cancer cells by one of many mechanisms: activation of poly ADP-ribose polymerase (PARP) and/or depletion of intracellular ATP; generation of DNA damage that cannot be repaired quickly enough to prevent cell death; depletion of intracellular reducing equivalents via their consumption by glutathione-dependent peroxidases; direct mitochondrial toxicity; direct membrane toxicity. Experiments exploring these concepts are underway. Other current efforts are focused on: continued investigation of pharmacologic ascorbic acid as an agent to inhibit tumor growth in animal models; in vivo imaging of hydrogen peroxide; initiation and continuation of phase II clinical trials, and continued characterization of clinical usage patterns and safety.

解释 口服时，抗坏血酸受三种生理机制的严格控制：吸收、组织转运和肾重吸收/排泄。根据本实验室进行的生物利用度实验，静脉注射抗坏血酸可绕过严格控制，直至肾脏恢复稳态。这些数据对癌症治疗具有令人惊讶的和新颖的意义。 30多年前，尤恩卡梅隆提出，抗坏血酸可能对治疗癌症患者有有益的作用。两届诺贝尔奖获得者莱纳斯·鲍林（Linus Pauling）也加入了他们的行列，他们发表了两个病例系列，表明每日大剂量抗坏血酸（10克）对某些晚期癌症患者的潜在益处。为了比较，请注意，当时抗坏血酸的推荐膳食允许量为每日60 mg，或治疗剂量的0.6%。Cameron-Pauling的数据受到批评，因为它们是回顾性的，没有安慰剂对照，部分主观，缺乏独立的病理学证实。 马约诊所的研究人员进行了两项双盲、安慰剂对照试验，每天使用10克抗坏血酸治疗晚期癌症患者，结果没有发现效果。基于这些数据，医生被强烈建议不要在癌症治疗中使用抗坏血酸。根据我们广泛的生物利用度数据，我们回顾了卡梅隆和同事以及马约诊所研究人员的实验。我们惊讶地发现，卡梅伦相关患者接受静脉注射和口服抗坏血酸，但马约诊所相关患者仅接受口服抗坏血酸。因此，治疗组之间的比较是无效的，抗坏血酸在癌症治疗中的问题需要重新评估。 根据我们的生物利用度数据和药代动力学模型，静脉注射抗坏血酸可产生比最大耐受口服剂量高70倍的血浆浓度。在体外，人体很容易达到的药理学抗坏血酸浓度可以杀死癌症，但不能杀死正常细胞。细胞外抗坏血酸、抗坏血酸自由基的氧化和过氧化氢的蛋白质依赖性形成介导杀伤。为了在不受抗坏血酸干扰的情况下检测过氧化氢，实验需要专门化学合成的过氧氧杂蒽酮，而这在市场上是买不到的。基于所获得的数据，我们提出并在体内验证了这样的假设：药理学抗坏血酸是在血管外空间而不是血液中优先形成抗坏血酸根的前药。同样，体内实验依赖于过氧氧杂蒽酮的合成。 同时，我们提出了一个全球性的假设，解释了为什么癌症细胞而不是正常细胞对抗坏血酸介导的过氧化氢形成的死亡敏感。过氧化氢在抗坏血酸和催化金属的存在下导致形成多种活性氧物质（ROS）。由此形成的活性氧物质可通过多种机制之一选择性地杀死癌细胞：激活聚ADP-核糖聚合酶（PARP）和/或耗尽细胞内ATP;产生不能足够快地修复以防止细胞死亡的DNA损伤;通过谷胱甘肽依赖性过氧化物酶消耗细胞内还原当量来耗尽细胞内还原当量;直接线粒体毒性;直接膜毒性。探索这些概念的实验正在进行中。 其他目前的努力集中在：继续研究药理学抗坏血酸作为一种药物，以抑制肿瘤生长的动物模型;在体内成像的过氧化氢;启动和继续第二阶段的临床试验，并继续表征临床使用模式和安全性。